Cycloserine is a second-line, broad-spectrum antibiotic used in the treatment of active pulmonary and extrapulmonary tuberculosis (TB) and urinary tract infections (UTIs). In the treatment of TB, it is given only when other antituberculars are ineffective and in cases needing retreatment. While cycloserine has activity against some genitourinary pathogens, it is seldom used clinically for these infections. Cycloserine also may be used to treat Mycobacterium avium complex (MAC)* when less hazardous drugs are ineffective. Cycloserine was approved by the FDA in 1956.
General Administration Information
For storage information, see the specific product information within the How Supplied section.
Tuberculosis
-Directly observed therapy (DOT) is recommended for all children as well as adolescents and adults living with HIV.
-Concomitant pyridoxine is recommended.
Route-Specific Administration
Oral Administration
-Absorption is modestly decreased by food; administer on an empty stomach.
Nervous system adverse effects reported with cycloserine include convulsions, drowsiness and somnolence, headache, tremor, dysarthria, vertigo, confusion and disorientation with memory impairment, psychosis possibly with suicidal ideation, character changes, hyper-irritability, aggression, paresis, hyperreflexia, paresthesias, peripheral neuropathy, major and minor (localized) seizures, and coma. Nervous system symptoms appear to be related to higher cycloserine doses (i.e., more than 500 mg/day); monitor patients receiving more than cycloserine 500 mg/day closely for such symptoms. Discontinue cycloserine if the patient develops symptoms of neurotoxicity. Anticonvulsant drugs or sedatives may be effective in controlling symptoms of neurotoxicity, such as seizures, anxiety, and tremor. Many of the neurotoxic effects of cycloserine can be both treated and prevented with pyridoxine administration.
Cycloserine has been associated in a few instances with vitamin B6 deficiency and/or folate deficiency, megaloblastic anemia, and sideroblastic anemia. If evidence of anemia develops during treatment, institute appropriate studies and therapy.
The sudden development of heart failure has been reported in patients receiving 1 to 1.5 g/day of cycloserine.
Rash has been reported with the use of cycloserine. Discontinue cycloserine if the patient develops allergic dermatitis.
Elevated hepatic enzymes, especially in patients with preexisting liver disease, have been reported with the use of cycloserine.
Cycloserine is contraindicated in patients with cycloserine hypersensitivity. Discontinue cycloserine or reduce the dosage if the patient develops allergic dermatitis.
Cycloserine is contraindicated in patients with alcoholism (excessive concurrent use of alcohol), seizure disorder, depression, severe anxiety, or psychosis. The risk of convulsions is increased in chronic alcoholics. Persons with alcoholism are at risk for cycloserine-induced neurotoxicity; administer pyridoxine concurrently to protect against the neurological adverse effects of cycloserine. Discontinue cycloserine if the patient develops symptoms of CNS toxicity.
Cycloserine is contraindicated in patients with severe renal impairment or renal failure. Cycloserine toxicity is closely related to excessive blood concentrations (more than 30 mcg/mL), as determined by high dosage or inadequate renal clearance. Monitor cycloserine concentrations at least weekly for patients with reduced renal function. Monitor renal function parameters. Persons with chronic renal disease are at risk for cycloserine-induced neurotoxicity; administer pyridoxine concurrently to protect against the neurological adverse effects of cycloserine.
Persons with human immunodeficiency virus (HIV) infection, diabetes mellitus, alcoholism, malnutrition, chronic renal disease, and advanced age are at risk for cycloserine-induced neurotoxicity; administer pyridoxine concurrently to protect against the neurological adverse effects of cycloserine.
Use lower initial dosages and carefully monitor renal function and blood concentrations in the geriatric adult, given that the toxicity of cycloserine is closely related to excessive blood concentrations, high dosage, or inadequate renal clearance. Geriatric adults may also be at risk for cycloserine-induced neurotoxicity; administer pyridoxine concurrently to protect against the neurological adverse effects of cycloserine.
Use cycloserine during pregnancy only if clearly needed. It is not known whether cycloserine can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. A study in 2 generations of rats given doses up to 100 mg/kg/day demonstrated no teratogenic effect in offspring.
Because of the potential for serious adverse reactions in a breast-feeding infant, discontinue breast-feeding or discontinue cycloserine, taking into account the importance of the drug to the mother. However, previous American Academy of Pediatrics recommendations considered cycloserine to be usually compatible with breast-feeding. It is estimated that a fully breast-fed infant would receive 1.7 mg/kg/day or 11% to 28% of a usual infant dosage.
Per the manufacturer, this drug has been shown to be active against most strains of the following microorganisms either in vitro and/or in clinical infections: Enterobacter sp., Escherichia coli, Mycobacterium tuberculosis
NOTE: The safety and effectiveness in treating clinical infections due to organisms with in vitro data only have not been established in adequate and well-controlled clinical trials.
This drug may also have activity against the following microorganisms: Mycobacterium avium, Mycobacterium bovis, Mycobacterium intracellulare, Mycobacterium kansasii, Mycobacterium marinum, Mycobacterium smegmatis, Mycobacterium ulcerans, Staphylococcus aureus (MSSA)
NOTE: Some organisms may not have been adequately studied during clinical trials; therefore, exclusion from this list does not necessarily negate the drug's activity against the organism.
For the treatment of drug-susceptible tuberculosis infection as part of combination therapy:
Oral dosage:
Adults: 10 to 15 mg/kg/day (Max: 1,000 mg/day) or 5 days/week PO divided once or twice daily. Start with an initial dose of 250 mg PO once daily and gradually increase as tolerated. Adjust dose based on serum peak concentration. Usual dose: 250 to 500 mg PO once or twice daily. Cycloserine is generally recommended as second-line therapy; duration is dependent on the site of involvement.
Infants*, Children*, and Adolescents*: 10 to 20 mg/kg/day (Max: 1,000 mg/day) or 5 days/week PO divided once or twice daily. Adjust dose based on serum peak concentration. Cycloserine is generally used as second-line therapy; duration is dependent on the site of involvement.
For the treatment of drug-resistant tuberculosis infection as part of combination therapy:
Oral dosage:
Adults: 10 to 15 mg/kg/day (Max: 1,000 mg/day) PO divided once or twice daily. Start with an initial dose of 250 mg PO once daily and gradually increase as tolerated. Adjust dose based on serum peak concentration.
Infants*, Children*, and Adolescents*: 10 to 20 mg/kg/day (Max: 1,000 mg/day) PO divided once or twice daily. Adjust dose based on serum peak concentration.
For the treatment of urinary tract infection (UTI):
Oral dosage:
Adults: 500 mg to 1 g/day PO divided once or twice daily. Usual dose: 250 mg PO twice daily. Adjust dose based on serum peak concentration. Max: 1 g/day.
Therapeutic Drug Monitoring:
-Monitor cycloserine serum concentrations at least weekly.
-Target serum peak concentrations of 20 to 35 mcg/mL to avoid central nervous system toxicity.
Maximum Dosage Limits:
-Adults
1 g/day PO.
-Geriatric
1 g/day PO.
-Adolescents
Safety and efficacy have not been established; 20 mg/kg/day (Max: 1 g/day) PO has been used off-label.
-Children
Safety and efficacy have not been established; 20 mg/kg/day (Max: 1 g/day) PO has been used off-label.
-Infants
Safety and efficacy have not been established; 20 mg/kg/day PO has been used off-label.
-Neonates
Safety and efficacy have not been established.
Patients with Hepatic Impairment Dosing
Specific guidelines for dosage adjustments in hepatic impairment are not available; it appears that no dosage adjustments are needed.
Patients with Renal Impairment Dosing
Cycloserine is contraindicated in patients with severe renal impairment. Monitor serum peak concentrations at least once weekly in patients with reduced renal function and adjust dose as needed.
Adult patients*
CrCl more than 50 mL/minute: No dosage adjustment needed. Consider monitoring serum peak concentrations.
CrCl 30 to 50 mL/minute: Monitor serum peak concentrations and adjust dose as needed.
CrCl less than 30 mL/minute: 250 mg PO once daily or 500 mg PO 3 times weekly; however, the appropriateness of 250 mg/day has not been established. Monitor serum peak concentrations and adjust dose as needed. Monitor for neurotoxicity.
Intermittent hemodialysis*
250 mg PO once daily or 500 mg PO 3 times weekly; however, the appropriateness of 250 mg/day has not been established. Monitor serum peak concentrations and adjust dose as needed. Monitor for neurotoxicity.
*non-FDA-approved indication
Ethionamide: (Moderate) Cycloserine interacts with ethionamide, possibly increasing the risk of developing CNS effects, especially seizures.
Isoniazid, INH: (Moderate) Concomitant administration of isoniazid, INH and cycloserine has resulted in adverse CNS effects. Dizziness and/or drowsiness occurred more frequently in patients receiving both drugs than in patients receiving cycloserine alone.
Isoniazid, INH; Pyrazinamide, PZA; Rifampin: (Moderate) Concomitant administration of isoniazid, INH and cycloserine has resulted in adverse CNS effects. Dizziness and/or drowsiness occurred more frequently in patients receiving both drugs than in patients receiving cycloserine alone.
Isoniazid, INH; Rifampin: (Moderate) Concomitant administration of isoniazid, INH and cycloserine has resulted in adverse CNS effects. Dizziness and/or drowsiness occurred more frequently in patients receiving both drugs than in patients receiving cycloserine alone.
Pyridoxine, Vitamin B6: (Moderate) Cycloserine can either interfere with the actions of pyridoxine, vitamin B6 or increase its clearance, which may result in a secondary niacin deficiency. It may be necessary to administer pyridoxine to patients receiving prolonged therapy with cycloserine to prevent the development of anemia or peripheral neuritis.
Teriflunomide: (Moderate) In vitro studies indicate that teriflunomide is a substrate of ABCG2 (breast cancer resistance protein, BCRP). Drugs that are inhibitors of BCRP, such as cyclosporine, may cause increases in teriflunomide plasma concentrations. Monitor patients for adverse effects, including symptoms serious liver injury and immunosuppression.
Vitamin B Complex Supplements: (Moderate) Cycloserine can either interfere with the actions of pyridoxine, vitamin B6 or increase its clearance, which may result in a secondary niacin deficiency. It may be necessary to administer pyridoxine to patients receiving prolonged therapy with cycloserine to prevent the development of anemia or peripheral neuritis.
Based on concentrations of cycloserine at the site of action and the susceptibility of the bacteria, cycloserine can be bactericidal or bacteriostatic. It is a structural analog of the amino acid D-alanine, which is important in the synthesis of peptidoglycan, the substance that gives cell walls their rigid, mechanical stability. Cycloserine competes with D-alanine for two enzymes, L-alanine racemase and D-alanine synthetase, both of which are involved in the incorporation of D-alanine into bacterial cell walls. Cycloserine inhibits both enzymes and peptidoglycan synthesis, resulting in a weak cell wall and eventually cell lysis.
Cycloserine has activity against various gram-positive and gram-negative organisms, with exceptional effectiveness in inhibiting Mycobacterium tuberculosis. In vitro studies reveal that cycloserine can inhibit the growth of enterococci, Escherichia coli, Staphylococcus aureus, Nocardia species, and Chlamydia if grown on D-alanine-free culture. The activity of cycloserine is inhibited by the presence of D-alanine. Cycloserine is effective against organisms that are resistant to other agents; there is no cross-resistance. Clinicians are advised to consult susceptibility data at the institution in which they practice to determine cycloserine activity.
Cycloserine is administered orally. The drug is not bound to plasma proteins and is distributed widely into the lungs, ascitic fluid, pleural fluid, and synovial fluid in concentrations similar to those in the serum. It also distributes into bile, sputum, and lymph tissue. Distribution into the CSF is approximately 50-80% of the current plasma concentration when meninges are uninflamed and 80-100% when meninges are inflamed. Cycloserine readily crosses the placenta and is distributed into amniotic fluid and breast milk. About 60-70% of an oral dose is renally excreted unchanged, with a plasma half-life of approximately 10 hours.
-Route-Specific Pharmacokinetics
Oral Route
The absorption of cycloserine is rapid following oral administration, with a bioavailability of 70-90%. Peak plasma levels occur 3-4 hours after a dose and average about 10 mcg/mL.
-Special Populations
Renal Impairment
Both plasma concentrations and the half-life of cycloserine are increased in patients with renal impairment, and dosage adjustments are required in these patients.